Process for the resolution of zopiclone and intermediate compounds

ABSTRACT

The present invention refers to a process for the resolution into one of its enantiomers of the racemate of compound of formula (I): 
                         
which comprises separating said one of its enantiomers from a diastereoisomeric salt of formula (II), which is formed by reaction of the racemic mixture with an optically active acetylated amino acid of formula (III). The invention also refers to new intermediates which are useful to carry out the process of the invention.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority from EP07380226.6, filed on Aug. 2,2007 and as a divisional of U.S. Pat. No. 7,772,396, filed on Oct. 3,2007 as U.S. application Ser. No. 11/866,584.

FIELD OF THE INVENTION

The present invention refers to a new process for the resolution intoone of its enantiomers of the racemic mixture of the compound zopiclone,6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine,and to intermediate compounds useful for carrying out said process.

BACKGROUND OF THE INVENTION

The compound6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-iperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazineof general formula (I):

also known by the name zopiclone, is a commercial product characterizedfor its hypnotic, sedative, tranquilizing, anxiolytic, muscle-relaxantand anticonvulsant properties. This compound was described for the firsttime in French patent document FR2166314, which also describes a processfor obtaining it as well as pharmaceutical compositions comprising saidactive ingredient.

The compound of formula (I) has an asymmetric carbon atom at the5-position of the 5H-pyrrolo[3,4-b]pyrazine ring-system and, as aresult, it must be considered, in racemic form, to consist of anequimolecular mixture of the laevorotatory and dextrorotatory forms. Ina racemic product, it is widely known that, often, one of the twoenantiomers is active and that an enhancement of the toxicity may belinked to this activity, the other enantiomer being both markedly lessactive or inactive and less toxic.

In the case of zopiclone, it was found that the dextrorotatoryenantiomer (S-enantiomer) is approximately twice active as the racemate,while having a lower toxicity than that of the racemate, but that thelaevorotatory isomer is both almost inactive and more toxic than theracemate.

The dextrorotatory isomer of zopiclone, also known as eszopiclone, maybe prepared from the corresponding racemate according to usual methods,such as chiral-phase chromatography, resolution of an optically activesalt, stereoselective enzymatic catalysis by means of an appropriatemicroorganism, or asymmetric synthesis.

The first reference describing a process for obtaining the differentenantiomers of zopiclone is EP0609210. More specifically, this documentrefers to a process for obtaining the dextrorotatory isomer of zopicloneby resolution of racemic zopiclone by using an optically active acid,namely D-(+)-O,O′-dibenzoyl-tartaric acid, working in the presence of anappropriate organic solvent, isolating the salt of the dextrorotatoryisomer, displacing this isomer from its salt and optionally, theconversion of said isomer into a pharmaceutically acceptable salt.

The scientific publication Chirality, 5, 419 (1993) and internationalapplications WO2005/079851, WO2005/060968 and WO2005/097132 describe theresolution of the racemic mixture of zopiclone to afford eszopiclone byusing malic acid as optically active acid in the presence of a mixtureof acetone and methanol as organic solvents. The resulting (S)-zopicloneD-malate salt is converted to optically pure eszopiclone by treatmentwith aqueous potassium carbonate and ethyl acetate, followed byseparation, crystallization and milling to the desired size.

The American patent application US2007/054914 refers to a method for theresolution of the racemic mixture of zopiclone by using di-p-toluoyltartaric acid as optically active acid.

However, in spite of the existence of processes allowing the resolutionof racemic zopiclone by fractionated crystallization using classicresolving agents, more specifically chiral acids, such as malic,dibenzoyltartaric and di-p-toluoyl tartaric acids, in organic solvents,these lead to compounds with low optical purity in a singlecrystallization and little reproducibility, what it makes necessaryfurther crystallization processes to obtain high optical purities.Consequently, there is a serious need to develop improved processeswhich allows obtaining enantiomers of a higher optical purity.

BRIEF DESCRIPTION OF THE INVENTION

The authors of the present invention have surprisingly found that theresolution of the racemic mixture of the compound zopiclone can beachieved enantioselectively by reacting it with an optically acetylatedamino acid. This process provides excellent diastereoisomeric excess andyields even in the first crystallization. Another advantage derived fromusing said acetylated amino acid, is that the eszopiclone salts obtainedin the process of the invention are water soluble, which makes easierthe work-up when isolating the desired enantiomer.

Therefore, an object of the present invention refers to a process(hereinafter referred as to the process of the invention) for theresolution into one of its enantiomers of the racemate of compound offormula (I):

which comprises separating said one of its enantiomers from adiastereoisomeric salt of formula (II):

wherein HX is an optically active acetylated amino acid of formula(III):

-   -   wherein:    -   n is 0, 1, 2 or 3,    -   R¹ is H, an alkyl group, an aryl group, a heteroaryl group,        CONH₂, COOH, SR² or    -   OR², wherein R² is a C₁-C₆ alkyl.

Another object of the invention refers to a process for the resolutioninto one of the enantiomers of the racemate of the compound of formula(I):

-   -   comprising the following steps:    -   a) reacting said racemate with any of the enantiomers of an        optically active acetylated amino acid of formula (III):

-   -   -   wherein n and R¹ are as defined above;

    -   b) isolating an optically pure diastereoisomeric salt of formula        (II):

-   -   -   wherein HX is the optically active acetylated amino acid of            formula (III); and

    -   c) separating an enantiomer of formula (I) from its        diastereoisomeric salt of formula (II).

Finally, another object of the present invention relates to thediastereoisomeric salts of formula (II) constituting the intermediatecompounds useful for carrying out the process described in the presentinvention. In a preferred aspect, said salts are (S)-zopicloneN-acetyl-D-glutamate, (S)-zopiclone N-acetyl-D-aspartate, (S)-zopicloneN-acetyl-D-methionate, (S)-zopiclone N-acetyl-L-glutamate, (S)-zopicloneN-acetyl-L-aspartate or (S)-zopiclone N-acetyl-L-methionate.

DETAILED DESCRIPTION OF THE INVENTION

In the above definition of compounds of formula (I) used in the presentinvention, the following terms have the meaning indicated:

“Alkyl” refers to a straight or branched hydrocarbon chain radicalconsisting of carbon and hydrogen atoms, containing no unsaturation,having one to eight carbon atoms, and which is attached to the rest ofthe molecule by a single bond, e.g., methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, n-pentyl, etc. The term “C₁-C₆ alkyl” is as definedfor alkyl but having one to six carbon atoms.

“Aryl” refers to a phenyl, naphthyl, indenyl, fenanthryl or anthracylradical, preferably phenyl or naphthyl radical.

“Heteroaryl” refers to an aromatic heterocyclic radical. The heterocyclerefers to a stable 3- to 15-membered ring which consists of carbon atomsand from one to five heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur, preferably a 4- to 8-membered ring withone or more heteroatoms, more preferably a 5- or 6-membered ring withone or more heteroatoms. Examples of such heterocycles include, but arenot limited to, azepines, benzimidazole, benzothiazole, furan,isothiazole, imidazole, indole, piperidine, piperazine, purine,quinoline, thiadiazole, tetrahydrofuran.

The present invention describes a new, effective and simple process forthe resolution into one of the enantiomers of the racemate of thecompound6-(5-chloro-2-pyridyl)-5-[(4-methyl-1-piperazinyl)carbonyloxy]-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyrazine by means of fractionated crystallization of new intermediatescorresponding to pure diastereoisomeric salts.

In a preferred embodiment of the invention, the optically activeacetylated amino acid of formula (III), also defined as HX, is selectedfrom N-acetyl-D-glutamic acid, N-acetyl-L-glutamic acid,N-acetyl-D-aspartic acid, N-acetyl-L-aspartic acid,N-acetyl-D-methionine and N-acetyl-L-methionine.

In a particular embodiment of the invention, the enantiomer obtainedaccording to the process of the invention is the (S)-enantiomer. In thiscase, the diastereoisomeric salt of formula (II) is selected from(S)-zopiclone N-acetyl-D-glutamate, (S)-zopiclone N-acetyl-D-aspartate,(S)-zopiclone N-acetyl-D-methionate, (S)-zopiclone N-acetyl-L-glutamate,(S)-zopiclone N-acetyl-L-aspartate and (S)-zopicloneN-acetyl-L-methionate.

In another particular embodiment of the invention, the enantiomerobtained according to the process of the invention is the(R)-enantiomer. In this case, the diastereoisomeric salt of formula (II)is selected from (R)-zopiclone N-acetyl-L-glutamate, (R)-zopicloneN-acetyl-L-aspartate, (R)-zopiclone N-acetyl-L-methionate, (R)-zopicloneN-acetyl-D-glutamate, (R)-zopiclone N-acetyl-D-aspartate and(R)-zopiclone N-acetyl-D-methionate.

The racemic compound base used as the starting material for theresolution proposed in this document can be obtained by any processknown in the state of the art. For example, said racemate can beobtained by a process such as described in French patent applicationFR2166314.

The resolution of the compound of formula (I):

is carried out by means of reacting the racemate or any mixture ofenantiomers of compound (I) with an optically pure acetylated amino acidof general formula (III):

wherein n is 0, 1, 2 or 3, and R¹ is H, an alkyl group, an aryl group, aheteroaryl group, CONH₂, COOH, SR² or OR², wherein R² is a C₁-C₆ alkyl,in an organic solvent or in a mixture of said organic solvents. Thusobtained are salts of formula (II):

wherein HX is the acetylated amino acid of formula (III) which, by meansof fractionated crystallization, is split into its purediastereoisomeric salts.

The formation of the diastereoisomeric salts from racemic mixtures ofthe compound of formula (I) with any of the enantiomers of acetylatedamino acids of formula (III) is carried out in the presence of anorganic solvent or in a mixture of organic solvents. In a preferredembodiment of the invention, the organic solvent is selected fromalcohols, ethers, esters, ketones, nitriles, halogenated solvents,aromatic solvents and mixtures thereof. Even in a more preferredembodiment, the organic solvent is selected form methanol, toluene,xylene, acetone, ethyl acetate, acetonitrile, tetrahydrofuran, isopropylacetate, ethyl formiate, methyl tertbutyl ether, diethylcarbonate,chlorobenzene, dichloromethane and mixtures thereof.

In a variant of the process, if the dextrorotatory enantiomer of theacetylated amino acid is used, then the (S)-zopiclone N-acetyl-D-aminoacid diastereoisomeric salt is firstly obtained. On the contrary, whenthe laevorotatory enantiomer of the acetylated amino acid is used, thenthe (R)-zopiclone N-acetyl-L-amino acid diastereoisomeric salt isfirstly obtained.

Thus, in a particular embodiment of the invention, whenN-acetyl-D-glutamic acid is used as optically active amino acid offormula (III), then (S)-zopiclone N-acetyl-D-glutamate is isolated inthe step b) of the process. In another particular embodiment, whenN-acetyl-L-glutamic acid is used as optically active amino acid offormula (III), then (R)-zopiclone N-acetyl-L-glutamate is isolated instep b). In another particular embodiment, when N-acetyl-D-aspartic acidis used as optically active amino acid of formula (III), then(S)-zopiclone N-acetyl-D-aspartate is isolated in step b). In anotherparticular embodiment, when N-acetyl-L-aspartic acid is used asoptically active amino acid of formula (III), then (R)-zopicloneN-acetyl-L-aspartate is isolated in step b). In another particularembodiment, when N-acetyl-D-methionine is used as optically active aminoacid of formula (III), then (S)-zopiclone N-acetyl-D-methionate isisolated in step b). In another particular embodiment, whenN-acetyl-L-methionine is used as optically active amino acid of formula(III), then (R)-zopiclone N-acetyl-L-methionate is isolated in step b).

Therefore, depending on the choice of the acetylated amino acidenantiomer of formula (III), one of the two possible diastereoisomericsalts is split in a first crystallization, the other diastereoisomericsalt remaining dissolved in the mother liquor, which could be alsoisolated. Therefore, another aspect of the invention refers to anadditional isolation step of the other optically pure diastereoisomericsalt of formula (II). This additional isolation step of the otherdiastereoisomeric salt comprises the concentration of the mother liquorgenerated upon isolating the first diastereoisomeric salt and thesubsequent crystallization so as to cause precipitation of the saidother diastereoisomeric salt.

The salts obtained in any of the cases described above can be purifiedfor the purpose of increasing their optical purity by simpleresuspension or recrystallization in a suitable solvent.

In a particular embodiment of the invention, the (R)-enantiomer obtainedfrom the process of the invention may be recycled in order to preparethe (S)-enantiomer. Thus, the process of the invention may furthercomprise an additional step of racemisation of the (R)-enantiomer toprepare the racemate of compound of formula (I). This step can becarried out by deprotonation of the chiral carbon of the (R)-enantiomer,thus obtaining a planar molecule which is susceptible to be convertedagain in a racemic compound. Once the racemate of formula (I) isobtained, then this compound is subjected to the steps a) to c)described above in order to isolate the (S)-enantiomer.

Another aspect of the present invention refers to an optically purediastereoisomeric salt of formula (II):

wherein HX is as defined above.

In a preferred embodiment, said salt of formula (II) is (S)-zopicloneN-acetyl-D-glutamate, (S)-zopiclone N-acetyl-D-aspartate, (S)-zopicloneN-acetyl-D-methionate, (S)-zopiclone N-acetyl-L-glutamate, (S)-zopicloneN-acetyl-L-aspartate or (S)-zopiclone N-acetyl-L-methionate.

The previously described process allows resolving the racemic mixture ofthe compound of formula (I) by obtaining any of the two enantiomers. Theyields and optical purity of the obtained products, the simplicity ofthe operations and the reproducibility of the process make it applicablefrom the industrial point of view.

The following examples are provided only as an additional illustrationof the invention and must not be taken as a definition of the limitsthereof.

EXAMPLES Example 1 Preparation of (S)-zopiclone N-acetyl-D-aspartate

A three-neck 500 ml flask was charged with 25 g of (±)-zopiclone (1 eq)and 11.3 g of N-acetyl-D-aspartic acid (1 eq). 363 ml of a mixture ofmethanol/toluene (1/1) were added. The reaction mixture was stirred for10 minutes at room temperature, then heated and maintained for 30minutes at reflux. The dispersion was slowly cooled and maintained forover 30 minutes at room temperature. The solid product was isolated byfiltration and washed with 10 ml of methanol and 10 ml of toluene. Thesolid was dried under vacuum to obtain 15.6 g of (S)-zopicloneN-acetyl-D-aspartate (43%) as a white product.

Diastereoisomeric excess (d.e.): 99.5% by chiral HPLC. Water content:0.6% w/w. Melting point: 186-189° C. [α]_(D) ²⁰: +55° (c 1% w/w water).IR (KBr, cm⁻¹): 3433, 1741, 1731, 1720, 1675, 1575, 1460, 1373, 1279,1255, 1031. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.96 (1H, d, 2.4 Hz),8.93 (1H, d, 2.4 Hz), 8.53 (1H, d, 2.4 Hz), 8.36 (1H, d, 9.2 Hz), 8.14(1H, wide signal), 8.09 (1H, dd, 9.2 Hz, 2.4 Hz), 7.78 (1H, s),4.47-4.41 (1H, m), 3.47 (1H, wide signal), 3.31 (1H, wide signal), 3.14(2H, wide signal), 2.62 (1H, dd, 16.4 Hz, 6.4 Hz), 2.50 (1H, dd, 16.4Hz, 6.4 Hz), 2.35 (1H, wide signal), 2.32 (1H, wide signal), 2.19 (1H,wide signal), 2.18 (3H, s), 1.89 (1H, wide signal), 1.81 (3H, s).¹³C-NMR (DMSO-d₆, 100 MHz) δ (ppm): 172.7, 171.8, 169.0, 163.1, 155.4,152.8, 148.6, 148.0, 147.8, 146.6, 143.4, 138.6, 127.1, 116.1, 79.1,53.7, 48.6, 45.2, 43.2, 36.6, 22.4. XRPD (2θ): main peaks at 14.7, 14.8,17.7, 18.3, 18.7, 19.2, 19.8, 21.5, 24.4, 25.1, 25.9, 26.2, 27.3,33.1±0.2.

Example 2 Preparation of (R)-zopiclone N-acetyl-D-aspartate

160 ml of a mixture of methanol/toluene at atmospheric pressure weredistilled from the mother liquors of the preparation of the example 1. Alight brown solid crystallized from the resulting mixture. Thedispersion was cooled at room temperature. The solid was isolated byfiltration and washed with 10 ml of methanol and 10 ml of toluene. Theproduct was dried under vacuum to obtain 15.8 g of white solid(R)-zopiclone N-acetyl-D-aspartate (44%) as an off-white solid.

d.e.: 86.3% by chiral HPLC. Water content: 6.3% w/w. Melting point:176-177° C. [α]_(D) ²⁰: −72.5° (c 1% w/w water). IR (KBr, cm⁻¹): 3433,3068, 2860, 1741, 1732, 1720, 1675, 1577, 1461, 1373, 1255, 1144, 1052,975. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.96 (1H, d, 2.8 Hz), 8.93 (1H,d, 2.8 Hz), 8.52 (1H, d, 2.8 Hz), 8.36 (1H, d, 9.2 Hz), 8.10 (1H, widesignal), 8.09 (1H, dd, 9.2 Hz, 2.8 Hz), 7.76 (1H, s), 4.46-4.41 (1H, m),3.47 (1H, wide signal), 3.31 (1H, wide signal), 3.14 (2H, wide signal),2.62 (1H, dd, 16.4 Hz, 6.0 Hz), 2.50 (1H, dd, 16.4 Hz, 6.4 Hz), 2.40(1H, wide signal), 2.32 (1H, wide signal), 2.19 (1H, wide signal), 2.16(3H, s), 1.88 (1H, wide signal), 1.81 (3H, s). ¹³C-NMR (DMSO-d₆, 100MHz) δ (ppm): 172.7, 171.8, 169.0, 163.1, 155.4, 152.8, 148.6, 148.0,147.8, 146.6, 143.4, 138.6, 127.1, 116.1, 79.1, 53.7, 48.6, 45.2, 43.3,36.6, 22.4. XRPD (2θ): main peaks at 5.3, 8.0, 10.6, 12.7, 14.1, 15.8,15.9, 17.1, 21.3, 24.2, 24.8, 25.5, 25.8±0.2.

Example 3 Preparation of (R)-Zopiclone N-Acetyl-L-Aspartate

A three-neck 100 ml flask was charged with 2 g of (±)-zopiclone (1 eq)and 0.9 g of N-acetyl-L-aspartic acid (1 eq), and a mixture of 29 ml ofmethanol/xylene (1/1) were added. The reaction mixture was stirred for10 minutes at room temperature, then heated and maintained for 30minutes at reflux, and then was cooled and the dispersion was maintainedfor over 30 minutes at room temperature. The solid product was isolatedby filtration and washed with 0.8 ml of methanol and 0.8 ml of xylene.The product was dried under vacuum to obtain 1.18 g of (R)-zopicloneN-acetyl-L-aspartate (41%) as a white solid.

d.e.: 91.8% by chiral HPLC. Water content: 0.6% w/w. Melting point:184-186° C. [α]_(D) ²⁰: −57.5° (c 1% w/w water). IR (KBr, cm⁻¹): 3413,3060, 2964, 1732, 1720, 1661, 1467, 1376, 1258, 1169, 1079. ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.96 (1H, d, 2.4 Hz), 8.93 (1H, d, 2.4 Hz),8.52 (1H, d, 2.4 Hz), 8.36 (1H, d, 9.2 Hz), 8.10 (1H, wide signal), 8.09(1H, dd, 9.2 Hz, 2.4 Hz), 7.76 (1H, s), 4.46-4.40 (1H, m), 3.47 (1H,wide signal), 3.31 (1H, wide signal), 3.14 (2H, wide signal), 2.62 (1H,dd, 16.4 Hz, 6.4 Hz), 2.50 (1H, dd, 16.4 Hz, 6.4 Hz), 2.39 (1H, widesignal), 2.31 (1H, wide signal), 2.19 (1H, wide signal), 2.15 (3H, s),1.85 (1H, wide signal), 1.81 (3H, s). ¹³C-NMR (DMSO-d₆, 100 MHz) δ(ppm): 172.7, 171.9, 169.0, 163.1, 155.4, 152.8, 148.6, 148.0, 147.8,146.6, 143.4, 138.6, 127.1, 116.1, 79.1, 53.8, 48.6, 45.2, 43.3, 36.7,22.4. XRPD (2θ): main peaks at 14.7, 14.8, 18.3, 18.7, 19.2, 19.8, 21.5,21.5, 24.4, 25.1, 25.9, 26.2, 27.3±0.2.

Example 4 Preparation of (R)-zopiclone N-acetyl-L-aspartate

A three-neck 250 ml flask was charged with 10 g of (±)-zopiclone (1 eq)and 4.5 g of N-acetyl-L-aspartic acid (1 eq). 87 ml of a mixture ofmethanol/toluene (1/1) were added. The reaction mixture was stirred for3 minutes at room temperature, then heated and maintained for 10 minutesat reflux temperature. The dispersion was slowly cooled and maintainedfor over 1 hour at room temperature. The solid product was isolated byfiltration and washed with 10 ml of methanol and 10 ml of toluene. Theproduct was dried under vacuum to obtain 6.7 g of (R)-zopicloneN-acetyl-L-aspartate (46%) as a white solid.

d.e.: 96.6% by chiral HPLC. Water content: 0.2% w/w. Melting point:181-186° C. [α]_(D) ²⁰: −62.5° (c 1% w/w water). IR (KBr, cm⁻¹): 3433,3067, 3006, 2860, 1740, 1731, 1720, 1675, 1576, 1460, 1373. ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.98 (1H, d, 2.8 Hz), 8.95 (1H, d, 2.8 Hz),8.54 (1H, d, 2.4 Hz), 8.38 (1H, d, 8.4 Hz), 8.14 (1H, wide signal), 8.11(1H, dd, 8.4 Hz, 2.4 Hz), 7.79 (1H, s), 4.49-4.43 (1H, m), 3.48 (1H,wide signal), 3.32 (1H, wide signal), 3.10 (2H, wide signal), 2.63 (1H,dd, 16.4 Hz, 6.0 Hz), 2.52 (1H, dd, 16.4 Hz, 6.4 Hz), 2.42 (1H, widesignal), 2.33 (1H, wide signal), 2.195 (1H, wide signal), 2.18 (s, 3H),1.91 (1H, wide signal), 1.83 (3H, s). ¹³C-NMR (DMSO-d₆, 100 MHz) δ(ppm): 172.7, 171.8, 169.0, 163.1, 155.4, 152.8, 148.6, 148.0, 147.8,146.6, 143.4, 138.6, 127.0, 116.1, 79.1, 53.7, 48.6, 45.2, 43.2, 36.6,22.4. XRPD (2θ): main peaks at 14.7, 18.3, 18.7, 19.2, 19.8, 21.4, 21.5,25.1, 25.9, 26.2, 27.3±0.2.

Example 5 Preparation of (S)-zopiclone N-acetyl-L-aspartate

80 ml of methanol/toluene of mother liquors of the preparation of(R)-zopiclone N-acetyl-L-aspartate of the example 4 were distilled atatmospheric pressure and white solid crystallized from the resultingmixture. 20 ml of fresh toluene were added. The mixture was cooled toroom temperature and maintained for over 30 minutes at this temperature.The product was isolated by filtration, washed twice with 10 ml oftoluene and dried under vacuum to obtain 6.2 g of (S)-zopicloneN-acetyl-L-aspartate (43%) as a white solid.

d.e.: 92.3% by chiral HPLC. Water content: 4.3% w/w. Melting point:173-179° C. [α]_(D) ²⁰: +93° (c 0.4% w/w acetone). IR (KBr, cm⁻¹): 3436,3059, 3025, 2968, 1743, 1732, 1724, 1660, 1470, 1377, 1079. ¹H-NMR(DMSO-d₆, 400 MHz), δ (ppm): 8.98 (1H, d, 2.8 Hz), 8.95 (1H, d, 2.8 Hz),8.54 (1H, d, 2.8 Hz), 8.38 (1H, d, 9.2 Hz), 8.14 (1H, wide signal), 8.11(1H, dd, 9.2 Hz, 2.8 Hz), 7.84 (1H, s), 4.48-4.43 (1H, m), 3.48 (1H,wide signal), 3.33 (1H, wide signal) 3.16 (2H, wide signal), 2.63 (1H,dd, 16.4 Hz, 6.4 Hz), 2.52 (1H, dd, 16.4 Hz, 6.8 Hz), 2.41 (1H, widesignal), 2.333 (1H, wide signal), 2.18 (s, 3H), 2.17 (1H, wide signal),1.91 (1H, wide signal), 1.83 (3H, s). ¹³C-NMR (DMSO-d₆, 100 MHz), δ(ppm): 172.7, 171.8, 169.0, 163.1, 155.4, 152.8, 148.6, 148.0, 147.8,146.6, 143.4, 138.6, 127.0, 116.1, 79.1, 53.7, 48.6, 45.2, 43.3, 36.6,22.4. XRPD (2θ): main peaks at 5.3, 7.9, 10.6, 12.7, 15.7, 17.0, 17.1,17.3, 18.8, 21.3, 24.3, 24.8, 25.6, 26.4, 29.1±0.2.

Example 6 Preparation of (S)-zopiclone N-acetyl-D-glutamate

A reaction flask was charged with 11.2 g of (±)-zopiclone (1 eq), 4.9 gof N-acetyl-D-glutamic acid (0.9 eq) and 830 ml of acetone. The mixturewas heated to reflux and the dispersion was maintained for 1 hour atthis temperature. The warm solution was filtered to obtain a clearsolution. The solution was concentrated to one half at atmosphericpressure. The solution was cooled and at about 46° C. white solidcrystallizes. The slurry was cooled at room temperature and maintainedfor 30 minutes. The solid product was isolated by filtration and washedwith 2 ml of acetone. The product was dried under vacuum to obtain 5.9 gof (S)-zopiclone N-acetyl-D-glutamate (40%) as a white solid.

d.e.: 89.7% by chiral HPLC. Water content: 0.75% w/w. Melting point:169-171° C. [α]_(D) ²⁰: +60° (c 1% w/w water). IR (KBr, cm⁻¹): 3422,3334, 3003, 2941, 2875, 1758, 1724, 1670, 1578, 14601, 1374, 1086.¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.98 (1H, d, 2.4 Hz), 8.95 (1H, d,2.4 Hz), 8.54 (1Hd, 2.8 Hz), 8.38 (1H, d, 9.2 Hz), 8.11 (1H, dd, 9.2 Hz,2.8 Hz), 8.10 (1H, wide signal) 7.79 (1H, s), 4.20-4.15 (1H, m), 3.48(1H, wide signal), 3.29 (1H, wide signal), 3.13 (2H, wide signal),2.40-2.20 (4H, m), 2.11 (3H, s), 2.08 (1H, wide signal), 1.94 (1H, m),1.84 (3H, s), 1.81-1.71 (2H, m). ¹³C-NMR (DMSO-d₆, 100 MHz), δ (ppm):173.7, 173.5, 169.3, 163.1, 155.4, 152.8, 148.6, 148.0, 147.7, 146.6,143.4, 138.6, 127.0, 116.1, 79.1, 53.9, 51.2, 45.5, 43.5, 30.2, 26.4,22.3. XRPD (2θ): main peaks at 3.4, 12.1, 13.6, 17.0, 18.4, 18.9, 19.1,19.2, 19.8, 20.08, 20.4, 22.0, 22.9, 24.1, 24.5, 25.4, 26.5, 27.3±0.2.

Example 7 Preparation of (R)-zopiclone N-acetyl-L-glutamate

A reaction flask was charged with 5 g of (±)-zopiclone (1 eq), 2.4 g ofN-acetyl-L-glutamic acid (1 eq) and 186 ml of acetone. The mixture washeated to reflux and the dispersion was maintained for 30 min at thistemperature. The solution was cooled at 35-37° C. and maintained 30 min.The suspension was cooled at room temperature. The product was isolatedby filtration and washed twice with 5 ml of acetone. The product wasdried under vacuum to obtain 3.6 g of (R)-zopiclone N-acetyl-L-glutamate(48%) as a white solid.

d.e.: 89.2% by chiral HPLC. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.96 (1H,d, 2.4 Hz), 8.93 (1H, d, 2.4 Hz), 8.52 (1H, d, 2.8 Hz), 8.36 (1H, d, 8.8Hz), 8.10 (1H, dd, 8.8 Hz, 2.8 Hz), 8.08 (1H, wide signal) 7.76 (1H, s),4.18-4.13 (1H, m), 3.46 (1H, wide signal), 3.28 (1H, wide signal), 3.11(2H, wide signal), 2.31-2.20 (4H, m), 2.10 (3H, s), 2.07 (1H, widesignal), 1.96-1.89 (1H, m), 1.82 (3H, s), 1.80-1.70 (2H, m).

Example 8 Preparation of (S)-zopiclone N-acetyl-D-methionate

A reaction flask was charged with 10.2 g of (±)-zopiclone (1 eq), 5 g ofN-acetyl-D-methionine (1 eq) and 300 ml of ethyl acetate. The mixturewas heated to reflux and the solution was maintained for 30 min at thistemperature. The solution was cooled and at about 66° C. solidcrystallized. The suspension was cooled and maintained for 1 hour atroom temperature. The product was isolated by filtration and washedtwice with 3 ml of ethyl acetate. The product was dried under vacuum toobtain 6.9 g of (S)-zopiclone N-acetyl-D-methionate (46%) as a whitesolid.

d.e.: 98.4% by chiral HPLC. Water content: 0.09% w/w. Melting point:171-172° C. [α]_(D) ²⁰: +77.5° (c 1% w/w acetone). IR (KBr, cm⁻¹): 3292,3064, 2915, 1740, 1731, 1720, 1668, 1461, 1373, 1090. ¹H-NMR (DMSO-d₆,400 MHz) δ (ppm): 8.98 (1H, d, 2.8 Hz), 8.95 (1H, d, 2.8 Hz), 8.54 (1H,d, 2.8 Hz), 8.37 (1H, d, 9.2 Hz), 8.13 (1H, wide signal), 8.11 (1H, dd,9.2 Hz, 2.8 Hz), 7.79 (1H, s), 4.30-4.24 (1H, m), 3.47 (1H, widesignal), 3.28 (1H, wide signal), 3.13 (2H, wide signal), 2.51-2.43 (2H,m), 2.31 (1H, wide signal), 2.22 (1H, wide signal), 2.11 (3H, s), 2.06(1H, wide signal), 2.03 (3H, s), 1.95-1.93 (1H, m), 1.84 (3H, s),1.81-1.71 (2H, m). ¹³C-NMR (DMSO-d₆, 100 MHz), δ (ppm): 173.5, 169.4,163.1, 155.4, 152.8, 148.6, 148.0, 147.7, 146.6, 143.4, 138.6, 127.0,116.1, 79.1, 54.0, 51.0, 45.6, 43.6, 30.7, 29.7, 22.4, 14.5. XRPD (2θ):main peaks at 3.3, 6.5, 11.8, 13.0, 13.9, 18.5, 18.7, 19.0, 19.1, 19.3,19.8, 20.0, 22.0, 22.2, 26.4, 27.1±0.2.

Example 9 Preparation of (R)-zopiclone N-acetyl-D-methionate

290 ml of ethyl acetate at atmospheric pressure were distilled from themother liquors of the preparation of (S)-zopiclone N-acetyl-D-methionateof the example 8. The product crystallized from the concentrate solutionat about 32° C. The mixture was cooled to room temperature andmaintained for over 30 minutes. The product was isolated by filtrationand washed twice with 3 ml of ethyl acetate. The product was dried undervacuum obtaining 4.2 g of (R)-zopiclone N-acetyl-D-methionate (28%) asan off-white solid.

d.e.: 82.6% by chiral HPLC. Water content: 1.7% w/w. Melting point:162-164° C. [α]_(D) ²⁰: −95° (c 1% w/w water). IR (KBr, cm⁻¹): 3447,3305, 2942, 2790, 1740, 1730, 1716, 1668, 1659, 1655, 1462, 1372, 1143,1046. ¹H-NMR (DMSO-d₆, 400 MHz) δ (ppm): 8.96 (1H, d, 2.8 Hz), 8.93 (1H,d, 2.8 Hz), 8.5 (1H, d, 2.8 Hz), 8.36 (1H, d, 9.2 Hz), 8.11 (1H, widesignal), 8.09 (1H, dd, 9.2 Hz, 2.8 Hz), 7.77 (1H, s), 4.27-4.22 (1H, m),3.45 (1H, wide signal), 3.26 (1H, wide signal), 3.11 (2H, wide signal),2.49-2.30 (2H, m), 2.30 (1H, wide signal), 2.19 (1H, wide signal), 2.08(3H, s), 2.04 (1H, wide signal), 2.01 (3H, s), 1.92-1.89 (1H, m), 1.82(3H, s), 1.79-1.69 (2H, m). ¹³C-NMR (DMSO-d₆, 100 MHz), δ (ppm): 173.5,169.4, 163.1, 155.4, 152.8, 148.6, 148.0, 147.7, 146.6, 143.4, 138.6,127.0, 116.1, 79.1, 54.0, 51.0, 45.6, 43.6, 30.7, 29.7, 22.4, 14.5. XRPD(2θ): main peaks at 3.3, 3.4, 11.9, 16.0, 16.7, 18.2, 18.8, 18.9, 20.0,20.7, 21.3, 21.6, 25.3, 25.6, 25.8, 26.1, 26.9, 27.6±0.2.

Example 10 Preparation of eszopiclone from (S)-zopicloneN-acetyl-L-aspartate

45 ml of dichloromethane were added to a solution of 3 g of(S)-zopiclone N-acetyl-L-aspartate in 6 ml of water at room temperature.The mixture is basified to pH 10 with a solution of 40% aqueouspotassium carbonate. The aqueous layer is decanted and extracted with 45ml of dichloromethane. Organic layers were joined together andconcentrated under vacuum until dryness obtaining 2.04 g of eszopiclone(100%) as a white solid.

Enantiomeric excess (e.e.): 99.3% by chiral HPLC. Water content: 0.02%w/w. Melting point: 190-192° C. [α]_(D) ²⁰: +115° (c 1% w/w acetone). IR(KBr, cm⁻¹): 2942, 2790, 1730, 1715, 1470, 1463, 1372, 1086. ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.98 (1H, d, 2.8 Hz), 8.95 (1H, d, 2.8 Hz),8.53 (1H, d, 2.8 Hz), 8.37 (1H, d, 9.2 Hz), 8.10 (1H, dd, 9.2 Hz, 2.8Hz), 7.79 (1H, s), 3.47 (1H, wide signal), 3.26 (1H, wide signal), 3.12(2H, wide signal), 2.30 (1H, wide signal), 2.20 (1H, wide signal), 2.09(3H, s), 2.04 (1H, wide signal), 1.76 (1H, wide signal). ¹³C-NMR(DMSO-d₆, 100 MHz), δ (ppm): 163.1, 155.4, 152.8, 148.6, 148.0, 147.8,146.6, 143.4, 138.6, 127.0, 116.1, 79.1, 54.0, 45.7, 43.6. XRPD (2θ):main peaks at 9.9, 12.5, 16.0, 16.1, 18.0, 19.0, 20.1, 21.3, 25.6, 25.8,27.6, 29.8±0.2.

Example 11 Preparation of (R)-zopiclone from (R)-zopicloneN-acetyl-L-aspartate

6 ml of water and 45 ml of dichloromethane were added to 3 g of(R)-zopiclone N-acetyl-L-aspartate at room temperature. The mixture isbasified to pH 10 with a solution of 40% aqueous potassium carbonate.The aqueous layer is decanted and extracted with 45 ml ofdichloromethane. The combined organic layers were concentrated undervacuum until dryness obtaining 2.15 g of (R)-zopiclone (100%) as a whitesolid. e.e.: 100% by chiral HPLC. [α]_(D) ²⁰: −125° (c 1% w/w acetone).IR (KBr, cm⁻¹): 2942, 2790, 1730, 1715, 1462, 1371, 1086. ¹H-NMR(DMSO-d₆, 400 MHz) δ (ppm): 8.98 (1H, d, 2.4 Hz), 8.95 (1H, d, 2.4 Hz),8.53 (1H, d, 2.8 Hz), 8.37 (1H, d, 9.2 Hz), 8.11 (1H, dd, 9.2 Hz, 2.8Hz), 7.79 (1H, s), 3.50 (1H, wide signal), 3.26 (1H, wide signal), 3.12(2H, wide signal), 2.30 (1H, wide signal), 2.20 (1H, wide signal), 2.09(3H, s), 2.04 (1H, wide signal), 1.76 (1H, wide signal). ¹³C-NMR(DMSO-d₆, 100 MHz), δ (ppm): 163.0, 155.4, 152.8, 148.6, 148.0, 147.7,146.6, 143.4, 138.6, 127.0, 116.1, 79.1, 54.0, 45.7, 43.6. XRPD (2θ):main peaks at 5.0, 9.9, 12.5, 16.0, 16.1, 18.0, 19.0, 20.0, 21.3, 25.6,27.6, 29.7±0.2.

Example 12 Preparation of eszopiclone from (S)-zopicloneN-acetyl-D-aspartate

2.7 ml of a 40% aqueous solution of potassium carbonate were added to asolution of 2 g of (S)-zopiclone N-acetyl-D-aspartate in 18 ml of waterin about 30 minutes at room temperature. The slurry was maintained for1.5 hours at this temperature. The product was isolated by filtrationand washed twice with 1.4 ml of water. The product was dried undervacuum at room temperature obtaining 1.29 g of eszopiclone (94%) as awhite solid. e.e.: 99.8% by chiral HPLC. Water content: 0.9% w/w.Melting point: 198-201° C. [α]_(D) ²⁰: +145° (c 1% w/w acetone).

Example 13 Crystallization of Eszopiclone

1 g of crude eszopiclone was dissolved in 15 ml of methyl isobutylketone (MIBK) at about 114° C. The solution was cooled and seeded. Thesolid crystallized at about 98-100° C., the slurry was maintained for 30minutes at this temperature. Then it was cooled at room temperature. Theproduct was isolated by filtration and washed twice with 0.4 ml MIBK.The product was dried under vacuum obtaining 0.85 g of eszopiclone(85%). e.e.: 100% by chiral HPLC. Melting point: 195-198° C. [α]_(D) ²⁰:+140° (c 1% w/w acetone).

Example 14 Crystallization of Eszopiclone

2.2 g of crude eszopiclone were dissolved in 44 ml of methyl ethylketone (MEK) at about 76° C. The warm solution was filtered and 23 ml ofMEK were distilled. The solution was cooled at −5° C. and maintained for30 minutes at this temperature. The product was isolated by filtrationand washed twice with 0.4 ml MEK. The product was dried under vacuumobtaining 2.0 g of eszopiclone (91%). e.e.: 100% by chiral HPLC. Meltingpoint: 202-204° C. [α]_(D) ²⁰: +135° (c 1% w/w acetone).

1. A process for the racemic resolution of a compound of formula (I):

which comprises resolving a diastereoisomeric salt of formula (II):

wherein HX is an optically active acetylated amino acid of formula(III):

wherein: n is 0, 1, 2 or 3, R¹ is H, an alkyl group, an aryl group, aheteroaryl group, CONH₂, COOH, SR² or OR², wherein R² is a C₁-C₆ alkyl.2. The process according to claim 1 wherein the optically activeacetylated amino acid of formula (III) is selected fromN-acetyl-D-glutamic acid, N-acetyl-L-glutamic acid, N-acetyl-D-asparticacid, N-acetyl-L-aspartic acid, N-acetyl-D-methionine andN-acetyl-L-methionine.
 3. The process according to claim 1 wherein thecompound of formula (I) is the (S)-enantiomer.
 4. The process accordingto claim 3 wherein the diastereoisomeric salt of formula (II) is(S)-zopiclone N-acetyl-D-glutamate, (S)-zopiclone N-acetyl-D-aspartate,(S)-zopiclone N-acetyl-D-methionate, (S)-zopiclone N-acetyl-L-glutamate,(S)-zopiclone N-acetyl-L-aspartate or (S)-zopicloneN-acetyl-L-methionate.
 5. The process according to claim 1 wherein thecompound of formula (I) is the (R)-enantiomer.
 6. The process accordingto claim 5 wherein the diastereoisomeric salt of formula (II) is(R)-zopiclone N-acetyl-L-glutamate, (R)-zopiclone N-acetyl-L-aspartateor (R)-zopiclone N-acetyl-L-methionate, (R)-zopicloneN-acetyl-D-glutamate, (R)-zopiclone N-acetyl-D-aspartate or(R)-zopiclone N-acetyl-D-methionate.
 7. A process for the racemicresolution of a compound of formula (I):

comprising the following steps: a) reacting said racemate with any ofthe enantiomers of an optically active acetylated amino acid of formula(III):

wherein: n is 0, 1, 2 or 3, R¹ is H, an alkyl group, an aryl group, aheteroaryl group, CONH₂, COOH, SR² or OR², wherein R² is a C₁-C₆ alkyl;b) isolating an optically pure diastereoisomeric salt of formula (II):

wherein HX is the optically active acetylated amino acid of formula(III); and c) separating an enantiomer of formula (I) from itsdiastereoisomeric salt of formula (II).
 8. The process according toclaim 7 wherein the organic solvent is selected from alcohols, ethers,esters, ketones, nitriles, halogenated solvents, aromatic solvents andmixtures thereof.
 9. The process according to claim 8 wherein theorganic solvent is selected form methanol, toluene, xylene, acetone,ethyl acetate, acetonitrile, tetrahydrofuran, isopropyl acetate, ethylformate, methyl tert-butyl ether, diethylcarbonate, chlorobenzene,dichloromethane and mixtures thereof.
 10. The process according to claim7 wherein the optically pure diastereoisomeric salt of formula (II)isolated in step b) is (S)-zopiclone N-acetyl-D-glutamate when thecompound of formula (III) is N-acetyl-D-glutamic acid.
 11. The processaccording to claim 7 wherein the optically pure diastereoisomeric saltof formula (II) isolated in step b) is (S)-zopicloneN-acetyl-D-glutamate when the compound of formula (III) isN-acetyl-D-glutamic acid, or (R)-zopiclone N-acetyl-L-glutamate when thecompound of formula (III) is N-acetyl-L-glutamic acid.
 12. The processaccording to claim 7 wherein the optically pure diastereoisomeric saltof formula (II) isolated in step b) is (S)-zopicloneN-acetyl-D-aspartate when the compound of formula (III) isN-acetyl-D-aspartic acid.
 13. The process according to claim 7 whereinthe optically pure diastereoisomeric salt of formula (II) isolated instep b) is (R)-zopiclone N-acetyl-L-aspartate when the compound offormula (III) is N-acetyl-L-aspartic acid.
 14. The process according toclaim 7 wherein the optically pure diastereoisomeric salt of formula(II) isolated in step b) is (S)-zopiclone N-acetyl-D-methionate when thecompound of formula (III) is N-acetyl-D-methionine.
 15. The processaccording to claim 7 wherein the optically pure diastereoisomeric saltof formula (II) isolated in step b) is (R)-zopicloneN-acetyl-L-methionate when the compound of formula (III) isN-acetyl-L-methionine.
 16. The process according to claim 7 comprisingan additional isolation step of the other optically purediastereoisomeric salt of formula (II), wherein the other optically purediastereoisomeric salt is the second diastereoisomeric salt that is leftafter the isolation of the first diastereoisomeric salt from theracemate.
 17. The process according to claim 16 wherein the additionalisolation step of the other diastereoisomeric salt of formula (II)comprises the concentration of the mother liquor generated uponisolating the first diastereoisomeric salt and subsequentcrystallization to obtain the other diastereoisomeric salt.
 18. Theprocess according to claim 17 wherein the other diastereoisomeric saltis (S)-zopiclone N-acetyl-L-glutamate, (S)-zopicloneN-acetyl-L-aspartate, (S)-zopiclone N-acetyl-L-methionate, (R)-zopicloneN-acetyl-D-glutamate, (R)-zopiclone N-acetyl-D-aspartate or(R)-zopiclone N-acetyl-D-methionate.
 19. The process according to claim1 which further comprises the racemisation of the (R)-enantiomer of thecompound of formula (I) to prepare the racemate of the compound offormula (I) and subsequently the isolation of the (S)-enantiomer of thecompound of formula (I) by: a) reacting said racemate with any of theenantiomers of an optically active acetylated amino acid of formula(III):

wherein: n is 0, 1, 2 or 3, R¹ is H, an alkyl group, an aryl group, aheteroaryl group, CONH₂, COOH, SR² or OR², wherein R² is a C₁-C₆ alkyl;b) isolating an optically pure diastereoisomeric salt of formula (II):

wherein HX is the optically active acetylated amino acid of formula(III); and c) separating the (S)-enantiomer of the compound of formula(I) from its diastereoisomeric salt of formula (II); and optionally d)isolating the pure (R)-form of the diastereoisomeric salt of formula(II).
 20. The process according to claim 16, wherein the other opticallypure diastereoisomeric salt is the second diastereoisomeric salt that isleft after the isolation of the first diastereoisomeric salt from theracemate.